1. Field of the Invention
This invention relates to heterocyclic derivatives, especially quinoline carbonyl pyrrolidines that bind with high selectivity and high affinity to the benzodiazepine site of GABAA receptors. This invention also relates to pharmaceutical compositions comprising such compounds and to the use of such compounds in treatment of central nervous system (CNS) diseases. This invention also relates to the use of these heterocyclic compounds in combination with one or more other CNS agents to potentiate the effects of the other CNS agents. Additionally this invention relates to the use such compounds as probes for the localization of GABAA receptors in tissue sections.
2. Description of the Related Art
The GABAA receptor superfamily represents one of the classes of receptors through which the major inhibitory neurotransmitter, xcex3-aminobutyric acid, or GABA, acts. Widely, although unequally, distributed through the mammalian brain, GABA mediates many of its actions through a complex of proteins called the GABAA receptor, which causes alteration in chloride conductance and membrane polarization.
A number of cDNAs for GABAA receptor subunits have been characterized. To date at least 6xcex1, 3xcex2, 3xcex3, 1xcex5, 1xcex4 and 2xcfx81 subunits have been identified. It is generally accepted that native GABAA receptors are typically composed of 2xcex1, 2xcex2, and 1xcex3 subunits (Pritchett and Seeburg Science 1989; 245:1389-1392 and Knight et. al., Recept. Channels 1998; 6:1-18). Evidence such as message distribution, genome localization and biochemical study results suggest that the major naturally occurring receptor combinations are xcex11xcex22xcex32, xcex12xcex23xcex32, xcex13xcex23xcex32, and xcex15xcex23xcex32 (Mohler et. al. Neuroch. Res. 1995; 20(5): 631-636).
Benzodiazepines exert their pharmacological actions by interacting with the benzodiazepine binding sites associated with the GABAA receptor. In addition to the benzodiazepine site, the GABAA receptor contains sites of interaction for several other classes of drugs. These include a steroid binding site, a picrotoxin site, and the barbiturate site. The benzodiazepine site of the GABAA receptor is a distinct site on the receptor complex that does not overlap with the site of interaction for GABA or for other classes of drugs that bind to the receptor (see, e.g., Cooper, et al., The Biochemical Basis of Neuropharmacology, 6th ed., 1991, pp. 145-148, Oxford University Press, New York). Early electrophysiological studies indicated that a major action of the benzodiazepines was enhancement of GABAergic inhibition. Compounds that selectively bind to the benzodiazepine site and enhance the ability of GABA to open GABAA receptor channels are agonists of GABA receptors. Other compounds that interact with the same site but negatively modulate the action of GABA are called inverse agonists. Compounds belonging to a third class bind selectively to the benzodiazepine site and yet have little or no effect on GABA activity, but can block the action of GABAA receptor agonists or inverse agonists that act at this site. These compounds are referred to as antagonists.
The important allosteric modulatory effects of drugs acting at the benzodiazepine site were recognized early and the distribution of activities at different receptor subtypes has been an area of intense pharmacological discovery. Agonists that act at the benzodiazepine site are known to exhibit anxiolytic, sedative, and hypnotic effects, while compounds that act as inverse agonists at this site elicit anxiogenic, cognition enhancing, and proconvulsant effects. While benzodiazepines have a long history of pharmaceutical use as anxiolytics, these compounds often exhibit a number of unwanted side effects. These may include cognitive impairment, sedation, ataxia, potentiation of ethanol effects, and a tendency for tolerance and drug dependence.
GABAA selective ligands may also act to potentiate the effects of other CNS active compounds. For example, there is evidence that selective serotonin reuptake inhibitors (SSRIs) may show greater antidepressant activity when used in combination with GABAA selective ligands than when used alone.
This invention provides heterocyclic compounds, especially quinoline carbonyl pyrrolidines that bind to the benzodiazepine site of the GABAA receptor, including human GABAA receptors.
Thus, the invention provides compounds of Formula I (shown below), and pharmaceutical compositions comprising compounds of Formula I.
The invention further comprises methods of treating patients suffering from CNS disorders with an effective amount of a compound of the invention. The patient may be a human or other mammal. Treatment of humans, domesticated companion animals (pets) or livestock animals suffering from CNS disorders with a therapeutically effective amount of a compound of the invention is encompassed by the invention.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds. This method comprises administering a therapeutically effective amount of a compound of the invention with another CNS active compound.
Additionally this invention relates to the use of the compounds of the invention as probes for the localization of GABAA receptors, for example, in tissue sections.
Accordingly, a broad aspect of the invention is directed to compounds of Formula I: 
or a pharmaceutically acceptable salt thereof wherein: 
represents: 
wherein:
A, B, D, and G are nitrogen or Cxe2x80x94R1;
with the proviso that not more than 2 of A, B, G, and D are nitrogen; and
E represents oxygen, sulfur or Nxe2x80x94R5;
R1 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, haloalkylhaloalkoxy, hydroxy, amino, xe2x80x94NH(R2), xe2x80x94N(R2)2, nitro, C1-C8 alkoxy and R2; wherein
R2 at each occurrence is independently selected from the group consisting of C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, and C5-C10 cycloalkynyl,
R5 is selected from the group consisting of R2, aryl, and C1-C8 alkoxy1, wherein R2, the aryl group and the C1-C8 alkoxy1, are optionally substituted with 1, 2, 3, or 4 groups selected from the group consisting of hydroxy, cyano, halogen, nitro, haloalkyl, haloalkoxy, amino, xe2x80x94NH(R2), and xe2x80x94N(R2)2;
Ra and Rb at each occurrence are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, haloalkyl, haloalkoxy, hydroxy, amino, xe2x80x94OR2 wherein R2 is substituted with 0-2 R6, xe2x80x94NH(R2) wherein R2 is substituted with 0-2 R6, xe2x80x94N(R2)2 wherein the R2 groups are independently substituted with 0-2 R6, substituted with 0-2 R6, phenyl substituted with 0-3 R6, xe2x80x94XR7, and Y;
W represents phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, wherein each is substituted with Rd, Rdxe2x80x2, and Rdxe2x80x3 which are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, haloalkyl, haloalkoxy, hydroxy, amino, R2 substituted with 0-2 R6, xe2x80x94OR2 substituted with 0-2 R6, xe2x80x94NH(R2) wherein R2 is substituted with 0-2 R6, phenyl substituted with 0-3 R6, xe2x80x94XR7, Y, and xe2x80x94N(C1-C6 alkyl1) (C1-C6 alkyl2) where each alkyl is independently substituted with 0-2 R6, or
alkyl1, alkyl2 and the nitrogen to which they are attached form a heterocycloalkyl ring substituted with 0-2 R6;
X at each occurrence is independently selected from the group consisting of xe2x80x94CH2xe2x80x94, xe2x80x94CHR8xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(O)mxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR8xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94C(O)NR8xe2x80x94, xe2x80x94S(O)mNHxe2x80x94, xe2x80x94S(O)mNR8xe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NR8C(O)xe2x80x94, xe2x80x94NHS(O)mxe2x80x94, and xe2x80x94NR8S(O)mxe2x80x94; wherein m is 0, 1, or 2;
R6 at each occurrence is independently selected from the group consisting of halogen, hydroxy, R2, xe2x80x94OR2, xe2x80x94NH(R2), xe2x80x94N(R2)2, xe2x80x94NHxe2x80x94(R2xe2x80x94Y), xe2x80x94N(R2)xe2x80x94(R2xe2x80x94Y), xe2x80x94NHxe2x80x94(R2xe2x80x94N(R2) (R2)) , xe2x80x94N(R2)xe2x80x94(R2xe2x80x94N(R2) (R2) morpholinyl, pyrrolidinyl, piperidinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, xe2x80x94S(O)m(R2) , haloalkyl, haloalkoxy, xe2x80x94CO(R2), xe2x80x94CONH(R2) , CON(R2)2, xe2x80x94XR7, and Y;
wherein m is 0, 1, or 2;
R7 and R8 at each occurrence independently carry the same definition as R2, wherein R7 and R8 are substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of oxo, hydroxy, halogen, amino, cyano, nitro, haloalkyl, haloalkoxy, xe2x80x94O(R2), xe2x80x94NH(R2), xe2x80x94N(R2)2, xe2x80x94NHC(O) (R2), xe2x80x94N(R2)C(O) (R2) , xe2x80x94NHS(O)m(R2) , xe2x80x94S(O)m(R2), xe2x80x94S(O)mNH(R2), and xe2x80x94S(O)mN(R2)2, and Yxe2x80x2;
wherein m is 0, 1, or 2;
Y and Yxe2x80x2 at each occurrence are independently selected from
5- to 8-membered carbocycles or heterocycles, which are saturated partially unsaturated, or aromatic and contain zero, one or two heteroatoms selected from N, O, and S, which carbocycles or heterocycles may be further substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, hydroxy, amino, nitro, cyano, R2, xe2x80x94OR2, xe2x80x94NH(R2), xe2x80x94N(R2)2, and xe2x80x94S(O)a(R2); wherein
a is 0, 1, or 2; and
Z is (CRaRb)n, wherein n is 0, 1, or 2.
The invention further provides methods for making the compounds of Formula I as well as intermediates useful in those methods.
Preferred compounds of Formula I are those where W is phenyl carrying Rd, Rdxe2x80x2, and Rdxe2x80x3 where one of Rd, Rdxe2x80x2, and Rdxe2x80x3 is hydrogen and the other two are are independently hydrogen, halogen, hydroxy, C1-C6 alkylamino(C1-C6)alkoxy, C1-C6 or alkoxy. Still other preferred compounds of Formula I are those where A, B, G, and D are CR1 and W is phenyl substituted with Rd, Rdxe2x80x2, and Rdxe2x80x3 where one of Rd, Rdxe2x80x2, and Rdxe2x80x3 is hydrogen and the other two are are independently hydrogen, halogen, hydroxy, C1-C6 alkylamino(C1-C6)alkoxy, C1-C6 or alkoxy.
A group of preferred compounds of Formula I designated as
compounds of Formula Ia herein are those wherein:
A, B, D, and G are nitrogen or Cxe2x80x94R1;
with the proviso that not more than 2 of A, B, G, and D are nitrogen; and
E represents oxygen, sulfur or Nxe2x80x94R5;
R1 at each occurrence is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, cyano, Haloalkyl, haloalkoxy, hydroxy, amino, xe2x80x94NH(C1-C6 alkyl), and xe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl);
R5 is selected from the group consisting of C1-C6 alkyl, aryl, and C1-C6 alkoxy, wherein the C1-C6 alkyl, the aryl group, and the C1-C6 alkoxy are optionally substituted with 1, 2, 3, or 4 groups selected from the group consisting of hydroxy, cyano, halogen, nitro, haloalkyl, haloalkoxy, amino, xe2x80x94NH(C1-C6 alkyl), and xe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl);
Ra and Rb at each occurrence are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, haloalkyl, haloalkoxy; hydroxy, amino, C1-C6 alkoxy substituted with 0-2 R6, xe2x80x94NH(C1-C6 alkyl) substituted with 0-2 R6, xe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl) wherein the C1-C6 alkyl groups are independently substituted with 0-2 R6, C1-C6 alkyl wherein the C1-C6 alkyl group is substituted with 0-2 R6, phenyl substituted with 0-3 R6, xe2x80x94XR7, and Y;
W represents phenyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, benzimidazolyl, naphthyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzo[b]thiophenyl, benz[d]isoxazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, or quinoxalinyl, wherein each is substituted with Rd, Rdxe2x80x2, and Rdxe2x80x3 which are independently selected from the group consisting of
hydrogen, halogen, cyano, nitro, haloalkyl, haloalkoxy, hydroxy, amino, C1-C6 alkyl substituted with 0-2 R6, C1-C6 alkoxy substituted with 0-2 R6, xe2x80x94NH(C1-C6 alkyl) wherein the C1-C6 alkyl is substituted with 0-2 R6, phenyl substituted with 0-3 R6, xe2x80x94XR7, Y, and xe2x80x94N(C1-C6 alkyl1) (C1-C6 alkyl2) wherein alkyl1 and alkyl2 are independently substituted with 0-2 R6, or
alkyl1, alkyl2 and the nitrogen to which they are attached form a heterocycloalkyl ring substituted with 0-2 R6;
X at each occurrence is independently selected from the group consisting of xe2x80x94CH2xe2x80x94, xe2x80x94CHR8xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(O)mxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NR8xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94C(O)NR8xe2x80x94, xe2x80x94S(O)mNHxe2x80x94, xe2x80x94S(O)mNR8xe2x80x94, xe2x80x94NHC(O)xe2x80x94, xe2x80x94NR8C(O)xe2x80x94, xe2x80x94NHS(O)mxe2x80x94, and xe2x80x94NR8S(O)mxe2x80x94; wherein m is 0, 1, or 2;
R6 at each occurrence is independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl), xe2x80x94NHxe2x80x94(C1-C6 alkyl-Y), xe2x80x94N(C1-C6 alkyl)xe2x80x94(C1-C6 alkyl-Y), xe2x80x94NHxe2x80x94(C1-C6 alkylxe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl)), xe2x80x94N(C1-C6 alkyl)xe2x80x94(C1-C6 alkyl-N(C1-C6 alkyl) (C1-C6 alkyl)), morpholinyl, pyrrolidinyl, piperidinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, xe2x80x94S(O)m(C1-C6 alkyl), haloalkyl, haloalkoxy, xe2x80x94CO(C1-C6 alkyl), xe2x80x94CONH(C1-C6 alkyl), CON(C1-C6 alkyl) (C1-C6 alkyl), xe2x80x94XR7, and Y; wherein
m is 0, 1, or 2;
R7 and R8 at each occurrence are independently C1-C8 alkyl, wherein R7 and R8 are substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of oxo, hydroxy, halogen, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-C6 alkoxy, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl), xe2x80x94NHC(O) (C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl)C(O) (C1-C6 alkyl), xe2x80x94NHS(O)m(C1-C6 alkyl), xe2x80x94S(O)m(C1-C6 alkyl), xe2x80x94S(O)mNH(C1-C6 alkyl), and xe2x80x94S(O)mN(C1-C6 alkyl) (C1-C6 alkyl), and Yxe2x80x2;
wherein m is 0, 1, or 2; and
Y and Yxe2x80x2 at each occurrence are independently selected from 5- to 8-membered carbocycles or heterocycles, which are saturated, partially unsaturated, or aromatic, and contain zero, one or two heteroatoms selected from N, O, and S, and which carboxycles or heterocycles may be further substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, hydroxy, amino, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl), and xe2x80x94S(O)a(C1-C6 alkyl); wherein
a is 0, 1, or 2; and
Z is (CRaRb)n, wherein n is 0, 1, or 2.
Preferred compounds of Formula Ia are those where A, B, G, and D are CR1 and W is phenyl is substituted with Rd, Rdxe2x80x2, and Rdxe2x80x3, where one of Rd, Rdxe2x80x2, and Rdxe2x80x3 is hydrogen and the other two are are independently hydrogen, halogen, hydroxy, C1-C6 alkylamino(C1-C6)alkoxy, C1-C6 or alkoxy.
Still other preferred compounds of Formula Ia include those where W is phenyl para substituted with C1-C6 alkylamino (C1-C6)alkoxy. Another preferred group of compounds of Formula Ia are those where W is phenyl or thienyl, more preferably phenyl, each of which is optionally mono- of disubstituted with groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, C1-C6 alkylamino (C1-C6)alkoxy, and C1-C6 alkoxy. More preferably, the phenyl and thienyl groups are mono- or disubstituted with C1-C2 alkyl, C1-C2 alkoxy, halogen, preferably chloro or fluoro, hydroxy, mono- or di(C1-C2) alkylamino(C1-C2)alkoxy, and C1-C6 alkoxy.
A preferred subclass of compounds of the invention is represented by compounds of Formula II, and the salts, prodrugs, and solvates thereof: 
wherein A, B, G, D, Ra, Rb, W, and Z are defined as in Formula I.
Preferred compounds of Formula II include those where A, B, G, and D are CR1. Other preferred compounds of Formula II are those where A, B, G, and D are CR1 and W is phenyl is substituted with Rd, Rdxe2x80x2, and Rdxe2x80x3, where one of Rd, Rdxe2x80x2, and Rdxe2x80x3 is hydrogen and the other two are are independently hydrogen, halogen, hydroxy, C1-C6 alkylamino(C1-C6)alkoxy, C1-C6 or alkoxy.
Still other preferred compounds of Formula II include those where W is phenyl para substituted with C1-C6 alkylamino(C1-C6)alkoxy. Another preferred group of compounds of Formula II are those where W is phenyl or thienyl, more preferably phenyl, each of which is optionally mono- of disubstituted with groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, C1-C6 alkylamino(C1-C6)alkoxy, and C1-C6 alkoxy. More preferably, the phenyl and thienyl groups are mono- or disubstituted with C1-C2 alkyl, C1-C2 alkoxy, halogen, preferably chloro or fluoro, hydroxy, mono- or di(C1-C2)alkylamino(C1-C2)alkoxy, and C1-C6 alkoxy.
More preferred compounds of Formula II, include compounds of Formula IIa: 
and the pharmaceutically acceptable salts thereof, wherein R1, Ra, Rb, W, and Z are defined as in for Formula I.
Particular compounds of Formula IIa are those compounds where W is phenyl or thienyl, substituted with Rd, Rdxe2x80x2, Rdxe2x80x3, which are defined as in Formula I. Preferred R1 groups in Formula IIa include hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, amino, mono- and di(C1-C6)alkylamino, nitro, C1-C6 alkoxy, and C1-C6 alkyl. More preferred R1 groups in Formula IIa are halogen, methyl, hydroxy, and methoxy; particularly preferred are fluoro and chloro.
Preferred compounds of Formula IIa include compounds of Formula IIb: 
wherein R1, Ra, and Rb, are defined as for Formula I and Rd, Rdxe2x80x2, and Rdxe2x80x3 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C1-C6 alkyl substituted with 0-2 R6, C1-C6 alkoxy substituted with 0-2 R6, xe2x80x94NH(C1-6 alkyl) substituted with 0-2 R6, xe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl) wherein each alkyl is independently substituted with 0-2 R6, xe2x80x94XR7, and Y;
X at each occurrence is independently selected from the group consisting of xe2x80x94CH2xe2x80x94, xe2x80x94CHR8xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94NR8xe2x80x94;
R6 at each occurrence is independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl), xe2x80x94NHxe2x80x94(C1-C6 alkyl-Y), xe2x80x94N(C1-C6 alkyl)xe2x80x94(C1-C6 alkyl-Y), xe2x80x94NHxe2x80x94(C1-C6 alkylxe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl)), xe2x80x94N(C1-C6 alkyl)xe2x80x94(C1-C6 alkyl-N(C1-C6 alkyl) (C1-C6 alkyl)), morpholinyl, pyrrolidinyl, piperidinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, xe2x80x94S(O)m(C1-C6 alkyl), trifluoromethyl, trifluoromethoxy, xe2x80x94CO(C1-C6 alkyl), xe2x80x94CONH(C1-C6 alkyl), CON(C1-C6 alkyl) (C1-C6 alkyl), xe2x80x94XR7, and Y; wherein
m is 0, 1, or 2;
R7 and R8 at each occurrence are independently C1-C8 alkyl, wherein R7 and R8 are substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of oxo, hydroxy, halogen, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-C6 alkoxy, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl); and
Y at each occurrence is independently selected from 5- to 8-membered carbocycles or heterocycles, saturated or unsaturated containing zero, one or two heteroatom(s) selected from N, O, and S, with the point of attachment being either carbon or nitrogen (where applicable), and which may be further substituted with one or more substituents selected from halogen, oxo, hydroxy, amino, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, and mono- or di C1-C6 alkylamino.
Preferred R1 groups in Formula IIb include hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, amino, mono- and di(C1-C6)alkylamino, nitro, C1-C6 alkoxy, and C1-C6 alkyl. More preferred R1 groups in Formula IIb are halogen, methyl, hydroxy, and methoxy; particularly preferred are fluoro and chloro.
Preferred compounds of Formula IIb include those where W is phenyl is substituted with Rd, Rdxe2x80x2, and Rdxe2x80x3, where one of Rd, Rdxe2x80x2, and Rdxe2x80x3 is hydrogen and the other two are are independently hydrogen, halogen, hydroxy, C1-C6 alkylamino(C1-C6)alkoxy, C1-C6 or alkoxy.
Still other preferred compounds of Formula IIb include those where W is phenyl para substituted with C1-C6 alkylamino(C1-C6)alkoxy. Another preferred group of compounds of Formula IIb are those where W is phenyl or thienyl, more preferably phenyl, each of which is optionally mono- of disubstituted with groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, C1-C6 alkylamino(C1-C6)alkoxy, and C1-C6 alkoxy. More preferably, the phenyl and thienyl groups are mono- or disubstituted with C1-C2 alkyl, C1-C2 alkoxy, halogen, preferably chloro or fluoro, hydroxy, mono- or di(C1-C2)alkylamino(C1-C2)alkoxy, and C1-C6 alkoxy.
More preferred W groups of Formula IIb include 4 -halophenyl and 3,4-dihalophenyl, particularly, 4-fluoro and 4-chlorophenyl. Still other more preferred W groups in Formula IIb are 4-alkoxyphenyl groups, particularly 4 -methoxyphenyl. Other more preferred W groups in Formula IIb are 2-(C1-C6)alkylphenyl such as 2-methyl and 2-ethylphenyl, haloalkoxyphenyl such as 3-bromopropoxyphenyl, 3 -alkoxyphenyl such as 3-methoxyphenyl, and 2-halophenyl, particularly 2-fluoro and 2-chlorophenyl. Still other more preferred w groups include 3,4-dihalophenyl groups, particularly where the halogens are fluoro or chloro. Other more prefered W groups are 2-halo-4-hydroxyphenyl and 2 -halo-4-alkoxyphenyl groups, particularly 2-fluoro and 2 -chloro-4-hydroxyphenyl and 2-fluoro-4-methoxy- or ethoxyphenyl.
Yet other preferred compounds of Formula IIb include those where Rb is hydrogen or C1-C2 alkyl and Ra is hydroxy (C1-C6) alkyl, 4-(C1-C6)alkyl-[1,4]diazepan-1-yl(C1-C6)alkyl, 4-(C1-C6)alkyl-piperazin-1-yl(C1-C6)alkyl, mono- or di (C1-C6) alkylamino (C1-C6) alkyl ((C1-C6) alkyl) amino (C1-C6) alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkylamino(C1-C6)alkyl, or pyrrolidin-1-yl or piperidin-1-yl (C1-C6)alkylamino(C1-C6)alkyl. Among these Ra groups, those that are more preferred include hydroxy(C1-C6)methyl, 4-(C1-C2)alkyl-[1,4]diazepan-1-ylmethyl, 4-(C1-C2)alkyl-piperazin-1 -ylmethyl, di (C1-C3) alkylamino (C2-C4) alkyl ((C1-C2)alkyl)aminomethyl, di (C1-C3) alkylamino (C2 -C4) alkylaminomethyl, or pyrrolidin-1-yl or piperidin-1-yl(C2 -C3)alkylaminomethyl. Particularly preferred Ra groups are hydroxy(C1-C6)methyl, 4-methyl-[1,4]diazepan-1-ylmethyl, 4 -methylpiperazin-1-ylmethyl, 2- (dimethyl- and diethylamino)ethyl(C1-C2 alkyl)aminomethyl, 2-(dimethyl- and diethylamino)ethylaminomethyl, or 2-(pyrrolidin-1-yl and piperidin-1-ylethyl)aminomethyl. Particularly preferred Rb groups of Formula IIb are hydrogen.
Other preferred compounds of Formula II are compounds of Formula IIc: 
and the pharmaceutically acceptable salts thereof wherein R1, Ra, Rb, W, and Z are defined as for Formula I.
Particular compounds of Formula IIc include compounds
where W is phenyl, substituted with Rd, Rdxe2x80x2 and Rdxe2x80x3 which are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C1-C6 alkyl substituted with 0-2 R6, C1-C6 alkoxy substituted with 0-2 R6, xe2x80x94NH(C1-6 alkyl) substituted with 0-2 R6, xe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl) wherein each alkyl is independently substituted with 0-2 R6, xe2x80x94XR7, and Y;
X at each occurrence is independently selected from the group consisting of xe2x80x94CH2xe2x80x94, xe2x80x94CHR8xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94NR8xe2x80x94;
R6 at each occurrence is independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl), xe2x80x94NHxe2x80x94(C1-C6 alkyl-Y), xe2x80x94N(C1-C6 alkyl)xe2x80x94(C1-C6 alkyl-Y), xe2x80x94NHxe2x80x94(C1-C6 alkylxe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl)), xe2x80x94N(C1-C6 alkyl)xe2x80x94(C1-C6 alkyl-N(C1-C6 alkyl) (C1-C6 alkyl)), morpholinyl, pyrrolidinyl, piperidinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, xe2x80x94S(O)m(C1-C6 alkyl), trifluoromethyl, trifluoromethoxy, xe2x80x94CO(C1-C6 alkyl), xe2x80x94CONH(C1-C6 alkyl), CON (C1-C6 alkyl) (C1-C6 alkyl), xe2x80x94XR7, and Y; wherein
m is 0, 1, or 2;
R7 and R8 at each occurrence independently carry the same definition as R2, wherein R7 and R8 are substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of oxo, hydroxy, halogen, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-C6 alkoxy, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl); and
Y at each occurrence is independently selected from 5- to 8-membered carbocycles or heterocycles, saturated or unsaturated containing zero, one or two heteroatom(s) selected from N, O, and S, with the point of attachment being either carbon or nitrogen (where applicable), and which may be further substituted with one or more substituents selected from halogen, oxo, hydroxy, amino, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, and mono- or di C1-C6 alkylamino.
Preferred compounds of Formula IIc include those where W is phenyl is substituted with Rd, Rdxe2x80x2, and Rdxe2x80x3, where one of Rd, Rdxe2x80x2, and Rdxe2x80x3 is hydrogen and the other two are are independently hydrogen, halogen, hydroxy, C1-C6 alkylamino(C1-C6)alkoxy, C1-C6 or alkoxy.
Still other preferred compounds of Formula IIc include those where W is phenyl para substituted with C1-C6 alkylamino(C1-C6)alkoxy. Another preferred group of compounds of Formula IIc are those where W is phenyl or thienyl, more preferably phenyl, each of which is optionally mono- of disubstituted with groups independently selected from C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, C1-C6 alkylamino(C1-C6)alkoxy, and C1-C6 alkoxy. More preferably, the phenyl and thienyl groups are mono- or disubstituted with C1-C2 alkyl, C1-C2 alkoxy, halogen, preferably chloro or fluoro, hydroxy, mono- or di(C1-C2)alkylamino(C1-C2)alkoxy, and C1-C6 alkoxy.
More preferred W groups of Formula IIc include 4 -halophenyl and 3,4-dihalophenyl, particularly, 4-fluoro and 4-chlorophenyl. Still other more preferred W groups in Formula IIc are 4-alkoxyphenyl groups, particularly 4 -methoxyphenyl. Other more preferred W groups in Formula IIc are 2-(C1-C6)alkylphenyl such as 2-methyl and 2-ethylphenyl, haloalkoxyphenyl such as 3-bromopropoxyphenyl, 3 -alkoxyphenyl such as 3-methoxyphenyl, and 2-halophenyl, particularly 2-fluoro and 2-chlorophenyl. Still other more preferred W groups include 3,4-dihalophenyl groups, particularly where the halogens are fluoro or chloro. Other more prefered W groups are 2-halo-4-hydroxyphenyl and 2 -halo-4-alkoxyphenyl groups, particularly 2-fluoro and 2 -chloro-4-hydroxyphenyl and 2-fluoro-4-methoxy- or ethoxyphenyl.
Yet other preferred compounds of Formula IIc include those where Rb is hydrogen or C1-C2 alkyl and Ra is hydroxy(C1-C6) alkyl, 4-(C1-C6) alkyl-[1,4]diazepan-1-yl(C1-C6)alkyl, 4-(C1-C6)alkyl-piperazin-1-yl(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkyl((C1-C6) alkyl)amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkylamino(C1-C6)alkyl, or pyrrolidin-1-yl or piperidin-1-yl(C1-C6)alkylamino(C1-C6)alkyl. Among these Ra groups, those that are more preferred include hydroxy(C1-C6)methyl, 4- (C1-C2)alkyl-[1,4]diazepan-1-ylmethyl, 4- (C1-C2) alkyl-piperazin-1 -ylmethyl, di (C1-C3)alkylamino(C2-C4)alkyl((C1-C2)alkyl)aminomethyl, di(C1-C3)alkylamino(C2-C4)alkylaminomethyl, or pyrrolidin-1-yl or piperidin-1-yl(C2 -C3)alkylaminomethyl. Particularly preferred Ra groups are hydroxy(C1-C6)methyl, 4-methyl-[1,4]diazepan-1-ylmethyl, 4 -methylpiperazin-1-ylmethyl, 2-(dimethyl- and diethylamino)ethyl(C1-C2 alkyl)aminomethyl, 2-(dimethyl- and diethylamino)ethylaminomethyl, or 2-(pyrrolidin-1-yl and piperidin-1-ylethyl)aminomethyl. Particularly preferred Rb groups of Formula IIc are hydrogen.
Still other preferred compounds of Formula II are compounds of Formula IId,: 
wherein R1, Ra, and Rb, are defined as for Formula I and Rd, Rdxe2x80x2 and Rdxe2x80x3 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, hydroxy, amino, and C1-C6 alkyl substituted with 0-2 R6, C1-C6 alkoxy substituted with 0-2 R6, xe2x80x94NH(C1-6 alkyl) substituted with 0-2 R6, xe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl) wherein each alkyl is independently substituted with 0-2 R6, xe2x80x94XR7, and Y;
X at each occurrence is independently selected from the group consisting of xe2x80x94CH2xe2x80x94, xe2x80x94CHR8xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, and xe2x80x94NR8xe2x80x94;
R6 at each occurrence is independently selected from the group consisting of halogen, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl), xe2x80x94NHxe2x80x94(C1-C6 alkyl-Y), xe2x80x94N(C1-C6 alkyl)xe2x80x94(C1-C6 alkyl-Y), xe2x80x94NHxe2x80x94(C1-C6 alkylxe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl)), xe2x80x94N(C1-C6 alkyl)xe2x80x94(C1-C6 alkyl-N(C1-C6 alkyl) (C1-C6 alkyl)), morpholinyl, pyrrolidinyl, piperidinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, xe2x80x94S(O)m(C1-C6 alkyl), trifluoromethyl, trifluoromethoxy, xe2x80x94CO(C1-C6 alkyl), xe2x80x94CONH(C1-C6 alkyl), CON(C1-C6 alkyl) (C1-C6 alkyl), xe2x80x94XR7, and Y; wherein
m is 0, 1, or 2;
R7 and R8 at each occurrence are independently C1-C8 alkyl, wherein R7 and R8 are substituted with 0, 1, 2, 3, or 4 substituents selected from the group consisting of oxo, hydroxy, halogen, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-C6 alkoxy, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl); and
Y at each occurrence is independently selected from 5- to 8-membered carbocycles or heterocycles, saturated or unsaturated containing zero, one or two heteroatom(s) selected from N, O, and S, with the point of attachment being either carbon or nitrogen (where applicable), and which may be further substituted with one or more substituents selected from halogen, oxo, hydroxy, amino, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, and mono- or di C1-C6 alkylamino.
Still other preferred compounds of Formula II are compounds of Formula IIE,: 
and the pharmaceutically acceptable salts thereof; wherein
R1 is hydrogen, halogen, C1-C2alkyl or C1-C2alkoxy;
Ra is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6alkoxy, haloalkyl, haloalkoxy, hydroxy C1-C6alkyl, mono- or di-(C1-C6)alkylamino, mono- or di-(C1-C6) alkyl3amino(C1-C6)alkyl where each alkyl3 may be substituted by mono- or di-(C1-C6)alkylamino, heterocycloalkyl(C1-C6)alkyl, heterocycloalkyl(C1-C6)alkylamino, and heterocycloalkyl which may be substituted by C1-C6alkyl;
Rb is selected from hydrogen, halogen, hydroxy, methyl, and ethyl,; and
W is phenyl, pyridyl, thienyl, or pyrimidinyl, each of which is substituted with Rd, Rdxe2x80x2, and Rdxe2x80x3 where Rd, Rdxe2x80x2, and Rdxe2x80x3 are independently selected from hydrogen, halogen, hydroxy, haloalkyl, haloalkoxy C1-C6 alkyl, C1-C6 alkoxy, mono- or di-(C1-C6)alkylamino, di(C1-C6) alkylamino(C1-C6)alkoxy, C3-C7 cycloalkylamino (C1-C6) alkoxy, and heteroaryl (C1-C6) alkoxy.
Preferred compounds of Formula IIE include those where Rb is hydrogen; one of Rd, Rdxe2x80x2, and Rdxe2x80x3 is hydrogen and the other two are independently selected from hydrogen, chloro, fluoro, hydroxy, methoxy, ethoxy, and methyl, ethyl, and C1-C3 alkylamino(C1-C2)alkoxy. Other preferred compounds of Formula IIE are those where Rb is hydrogen; Ra is hydrogen or hydroxy(C1-C3) alkyl, [(2-diethylamino-ethyl)-methyl-amino]methyl, or [(2-Diethylamino-ethyl)-methyl-amino]methyl. More preferred compounds of Formula IIE are those where Ra is hydroxymethyl or hydrogen, particularly hydroxymethyl.
Preferred compounds of formula IIE include those where
R1 is hydrogen, halogen, C1-C2alkyl or C1-C2alkoxy;
Ra is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6alkoxy, haloalkyl, haloalkoxy, hydroxy C1-C6alkyl, mono- or di-(C1-C6)alkylamino, mono- or di-(C1-C6) alkyl3amino(C1-C6)alkyl where each alkyl3 may be substituted by mono- or di-(C1-C6)alkylamino, and (C1-C6) alkylamino;
Rb is selected from hydrogen, halogen, hydroxy, methyl, and ethyl, and
W is phenyl, pyridyl, thienyl, or pyrimidinyl, each of which is substituted with Rd, Rdxe2x80x2, and Rdxe2x80x3, where Rd, Rdxe2x80x2, and Rdxe2x80x3 are independently selected from hydrogen, halogen, hydroxy, haloalkyl, haloalkoxy di(C1-C6)alkylamino(C1-C6)alkoxy, C1-C6 alkyl, C1-C6 alkoxy, mono- or di-(C1-C6) alkylamino, C1-C6 alkylamino(C1-C6)alkoxy, and C3-C7 cycloalkylamino (C1-C6) alkoxy.
Other preferred compounds of Formula IIE are those where Rb is hydrogen. More preferred compounds of Formula IIE are those where Rd, Rdxe2x80x2, and Rdxe2x80x3 are independently hydrogen, fluorine or hydroxyl. Still other more preferred compounds of Formula IIE are those where W is phenyl carrying Rd, Rdxe2x80x2, and Rdxe2x80x3 where one of Rd, Rdxe2x80x2, and Rdxe2x80x3 is hydrogen and the other two are independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, mono- or di-(C1-C6)alkylamino, C1-C6 alkylamino(C1-C6)alkoxy, or C3-C7 cycloalkylamino(C1-C6) alkoxy.
Particularly preferred compounds of Formula IIE are those where Rb is hydrogen and Ra is hydrogen, hydroxy(C1-C6)alkyl, 4-(C1-C6)alkyl-[1,4]diazepan-1-yl(C1-C6)alkyl, 4-(C1-C6)alkyl-piperazin-1-yl(C1-C6)alkyl, mono- or di (C1-C6)alkylamino(C1-C6)alkyl((C1-C6) alkyl)amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkylamino(C1-C6)alkyl, or pyrrolidin-1-yl or piperidin-1-yl (C1-C6)alkylamino(C1-C6)alkyl.
Still other particularly preferred compounds of Formula IIE are those where Rb is hydrogen and Ra is hydrogen, hydroxymethyl, [(2-diethylamino-ethyl)-methyl-amino]methyl, or [(2-Diethylamino-ethyl)-methyl-amino]methyl. Yet other particularly preferred compounds of Formula IIE are those where W is phenyl carrying Rd, Rdxe2x80x2, and Rdxe2x80x3 where one of Rd, Rdxe2x80x2, and Rdxe2x80x3 is hydrogen and the other two are independently hydrogen, halogen, hydroxy, C1-C6 alkylamino(C1-C6)alkoxy, C1-C6 or alkoxy.
Other preferred compounds of the invention are compounds of Formula III: 
and the pharmaceutically acceptable salts thereof, wherein G, D, E, Ra, Rb, W, and Z are defined as for Formula I.
Compounds of Formula III also include compounds of Formula IIIa: 
and the pharmaceutically acceptable salts thereof,
wherein R1, Ra, Rb, W, and Z are defined as for Formula IIb.
Particular compounds of Formula IIIa include compounds where W is phenyl, substituted with Rd, Rdxe2x80x2, and Rdxe2x80x3 (defined as for Formula IIb).
Still other preferred compounds of the invention are compounds of formula IV: 
wherein Ra and W are defined as in Formula I; and
R1 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-C8 alkoxy, and C1-C6 alkyl.
Other preferred compounds of formula IV include those where
W is defined as in formula I; R1 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-C8 alkoxy, and C1-C6 alkyl;
Ra is selected from the group consisting of hydrogen, xe2x80x94XR7, and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 0, 1, or 2 R6;
R6 is selected from the group consisting of xe2x80x94NHxe2x80x94(C1-C6 alkyl-Y), xe2x80x94N(C1-C6 alkyl)xe2x80x94(C1-C6 alkyl-Y), xe2x80x94NHxe2x80x94(C1-C6 alkylxe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl)), and xe2x80x94N(C1-C6 alkyl)xe2x80x94(C1-C6 alkylxe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl));
X is selected from the group consisting of xe2x80x94CH2xe2x80x94, xe2x80x94CHR8xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94C(O)N(C1-C6 alkyl)xe2x80x94, and xe2x80x94C(O)N(C1-C6 alkyl) (C1-C6 alkyl)xe2x80x94;
R7 and R8 at each occurrence are independently C1-C6 alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of hydroxy, amino, xe2x80x94NH(C1-C8 alkyl), xe2x80x94NH (C1-C8 alkyl) (C1-C8 alkyl); and
Y is selected from 5- to 8-membered carbocycles or heterocycles, which are saturated or unsaturated and contain zero, one or two heteroatoms selected from N, O, and S, with the point of attachment being either carbon or nitrogen (where applicable), and which may be further substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, hydroxy, amino, nitro, cyano, alkyl, C1-C6 alkoxy, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl) ( C1-C6 alkyl), and xe2x80x94S(O)a(C1-C6 alkyl); wherein
a is 0, 1, or 2.
Yet other preferred compounds of formula IV include those where: R1 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-C8 alkoxy, and C1-C6 alkyl;
Ra is selected from the group consisting of hydrogen, xe2x80x94XR7, and C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 0, 1, or 2 R6;
R6 is selected from the group consisting of xe2x80x94NHxe2x80x94(C1-C6 alkyl-Y), xe2x80x94N(C1-C6 alkyl)xe2x80x94(C1-C6 alkyl-Y), xe2x80x94NHxe2x80x94(C1-C6 alkylxe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl)), and xe2x80x94N(C1-C6 alkyl)xe2x80x94(C1-C6 alkylxe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl));
X is selected from the group consisting of xe2x80x94CH2xe2x80x94, xe2x80x94CHR8xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94C(O)N(C1-C6 alkyl)xe2x80x94, and xe2x80x94C(O)N(C1-C6 alkyl) (C1-C6 alkyl)xe2x80x94; and
R7 and R8 at each occurrence are independently C1-C6 alkyl optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of hydroxy, amino, xe2x80x94NH(C1-C8 alkyl), xe2x80x94NH(C1-C8 alkyl) (C1-C8 alkyl);
W is thiophene or phenyl, wherein each is unsubstituted or substituted with 1, 2, or 3 substituents selected from the group consisting of halogen, hydroxy, C1-C6 alkoxy, optionally substituted with amino, NH(C1-C6 alkyl), NH(C3-C6 cycloalkyl), halogen, and Y; and
Y is selected from 5- to 8-membered carbocycles or heterocycles, which are saturated or unsaturated and contain zero, one or two heteroatoms selected from N, O, and S, with the point of attachment being either carbon or nitrogen (where applicable), and which may be further substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, hydroxy, amino, nitro, cyano, C1-C6 alkyl, C1-C6 alkoxy, xe2x80x94NH(C1-C6 alkyl), xe2x80x94N(C1-C6 alkyl) (C1-C6 alkyl), and xe2x80x94S(O)a(C1-C6 alkyl); wherein
a is 0, 1, or 2.
In other preferred compounds of Formula IV,
Ra is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6alkoxy, haloalkyl, haloalkoxy, hydroxy C1-C6alkyl, mono- or di-(C1-C6)alkylamino, mono- or di-(C1-C6) alkyl3amino(C1-C6)alkyl where each alkyl3 may be substituted by mono- or di(C1-C6)alkylamino, heterocycloalkyl (C1-C6)alkyl, heterocycloalkyl(C1-C6)alkylamino, and heterocycloalkyl which may be substituted by C1-C6alkyl;
Rb is selected from hydrogen, halogen, hydroxy, methyl, and ethyl, and
W is phenyl, pyridyl, thienyl, or pyrimidinyl, each of which is substituted with Rd, Rdxe2x80x2, and Rdxe2x80x3, where Rd, Rdxe2x80x2, and Rdxe2x80x3 are independently selected from hydrogen, halogen, hydroxy, haloalkyl, haloalkoxy di(C1-C6)alkylamino(C1-C6)alkoxy, C1-C6 alkyl, C1-C6 alkoxy, mono- or di-(C1-C6)alkylamino, C1-C6 alkylamino(C1-C6)alkoxy, C3-C7 cycloalkylamino(C1-C6)alkoxy, and heteroaryl(C1-C6)alkoxy.
More preferred compounds of Formula IV are those where Rd, Rdxe2x80x2, and Rd are independently hydrogen, fluorine or hydroxyl. Still other more preferred compounds of Formula IV are those where W is phenyl carrying Rd, Rdxe2x80x2, and Rdxe2x80x3 where one of Rd, Rdxe2x80x2, and Rdxe2x80x3 is hydrogen and the other two are independently hydrogen, haloalkyl, haloalkoxy C1-C6 alkyl, C1-C6 alkoxy, mono- or di-(C1-C6)alkylamino, C1-C6 alkylamino(C1-C6)alkoxy, C3-C7 cycloalkylamino(C1-C6) alkoxy, or heteroaryl (C1-C6)alkoxy.
Particularly preferred compounds of Formula IV are those where Rb is hydrogen and Ra is hydrogen, hydroxy(C1-C6)alkyl, 4-(C1-C6)alkyl-[1,4]diazepan-1-yl (C1-C6) alkyl, 4 -(C1-C6)alkyl-piperazin-1-yl (C1-C6)alkyl, mono- or di (C1-C6)alkylamino(C1-C6)alkyl((C1-C6)alkyl)amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkylamino(C1-C6)alkyl, or pyrrolidin-1-yl or piperidin-1-yl(C1-C6)alkylamino(C1-C6)alkyl.
Still other particularly preferred compounds of Formula IV are those where Rb is hydrogen and Ra is hydrogen, hydroxymethyl, [(2-diethylamino-ethyl)-methyl-amino]methyl, or [(2-Diethylamino-ethyl)-methyl-amino]methyl. Yet other particularly preferred compounds of Formula IV are those where W is phenyl carrying Rd, Rdxe2x80x2, and Rdxe2x80x3 where one of Rd, Rdxe2x80x2, and Rdxe2x80x3 is hydrogen and the other two are independently hydrogen, halogen, hydroxy, C1-C6 alkylamino(C1-C6)alkoxy, C1-C6 or alkoxy.
In a preferred aspect, this invention provides quinolines that are substituted at the 2-position by a carbocyclic or heterocyclic group (such as optionally substituted phenyl or optionally substituted thienyl), at the 4-position by a pyrrolidinyl carbonyl group, and at the 6-position by a group R2 (defined above for Formula I). The pyrrolidine of the pyrrolidinyl carbonyl group is either unsubstituted or substituted at the 2 and/or 3 position. Preferred substituents at the 2 position of this pyrrolidine include hydroxymethyl, and aminoalkyl groups such as 2 -ethylamino-1-ethyl-1-methyl-aminomethyl, N-ethylpiperizine, 2-dimethylamino-1-ethyl-1-methyl-aminomethyl, (N-methylhomopiperizinyl)methyl, (N-methylpiperizinyl)methyl, N-piperidinylethylaminomethyl, and N-pyrrolidinylethylaminomethyl. Particularly preferred compounds having a substituent at the 2-position of the pyrrolidine group are those that are unsubstituted at the 3 -position. Preferred substituents at the 3-position of this pyrrolidine include hydroxy and halogen. Particularly preferred compounds having a substituent at the 3-position of the pyrrolidine group are those that are unsubstituted at the 2-position.
This invention relates to heterocyclic derivatives, in particular quinoline carbonyl pyrrolidines and more particularly, to such compounds that bind to the benzodiazepine site of GABAA receptors, including human GABAA receptors. This invention also includes such compounds that bind to the benzodiazepine site of GABAA receptors, including human GABAA receptors. Without wishing to be bound to any particular theory, it is believed that the interaction of the compounds of Formula I with the benzodiazepine site results in the pharmaceutical utility of these compounds.
The invention further comprises methods of treating patients in need of such treatment with a therapeutically effective amount of a compound of the invention sufficient to alter the symptoms of a CNS disorder. Compounds of the inventions that act as agonists at xcex12xcex22xcex32 and xcex12xcex23xcex32 receptor subtypes are useful in treating anxiety disorders such as panic disorder, obsessive compulsive disorder and generalized anxiety disorder; stress disorders including post-traumatic stress, and acute stress disorders. Compounds of the inventions that act as agonists at xcex12xcex23xcex32 and xcex12xcex23xcex32 receptor subtypes are also useful in treating depressive or bipolar disorders and in treating sleep disorders. Compounds of the invention that act as inverse agonists at the xcex15xcex23xcex32 receptor subtype or xcex11xcex22xcex32 and xcex15xcex23xcex32 receptor subtypes are useful in treating cognitive disorders including those resulting from Down Syndrome, neurodegenerative diseases such as Alzheimer""s disease and Parkinson""s disease, and stroke related dementia. Compounds of the invention that act as agonists at the xcex11xcex22xcex32 receptor subtype are useful in treating convulsive disorders such as epilepsy. Compounds that act as antagonists at the benzodiazepine site are useful in reversing the effect of benzodiazepine overdose and in treating drug and alcohol addiction.
The diseases, and/or disorders that can also be treated using compounds and compositions according to the invention include:
Depression, e.g. depression, atypical depression, bipolar disorder, depressed phase of bipolar disorder.
Anxiety, e.g. general anxiety disorder (GAD), agoraphobia, panic disorder xc2x1 agoraphobia, social phobia, specific phobia, Post traumatic stress disorder, obsessive compulsive disorder (OCD), dysthymia, adjustment disorders with disturbance of mood and anxiety, separation anxiety disorder, anticipatory anxiety acute stress disorder, adjustment disorders, cyclothymia.
Sleep disorders, e.g. sleep disorders including primary insomnia, circadian rhythm sleep disorder, dyssomnia NOS, parasomnias, including nightmare disorder, sleep terror disorder, sleep disorders secondary to depression and/or anxiety or other mental disorders, substance induced sleep disorder.
Cognition Impairment, e.g. cognition impairment, Alzheimer""s disease, Parkinson""s disease, mild cognitive impairment (MCI), age-related cognitive decline (ARCD), stroke, traumatic brain injury, AIDS associated dementia, and dementia associated with depression, anxiety or psychosis.
The invention also provides pharmaceutical compositions comprising compounds of the invention together with a pharmaceutically acceptable carrier. Such pharmaceutical compositions include packaged pharmaceutical compositions for treating disorders responsive to GABAA receptor modulation, e.g., treatment of anxiety, depression, sleep disorders or cognitive impairment by GABAA receptor modulation. The packaged pharmaceutical compositions include a container holding a therapeutically effective amount of at least one GABAA receptor modulator as described supra and instructions (e.g., labeling) indicating the contained GABAA receptor ligand is to be used for treating a disorder responsive to GABAA receptor modulation in the patient.
In a separate aspect, the invention provides a method of potentiating the actions of other CNS active compounds, which comprises administering an effective amount of a compound of the invention in combination with another CNS active compound. Such CNS active compounds include, but are not limited to the following: for anxiety, serotonin receptor (e.g. 5-HT1A) agonists and antagonists; for anxiety and depression, neurokinin receptor antagonists or corticotropin releasing factor receptor (CRF1) antagonists; for sleep disorders, melatonin receptor agonists; and for neurodegenerative disorders, such as Alzheimer""s dementia, nicotinic agonists, muscarinic agents, acetylcholinesterase inhibitors and dopamine receptor agonists. Particularly the invention provides a method of potentiating the antidepressant activity of selective serotonin reuptake inhibitors (SSRIs) by administering an effective amount of a GABA agonist compound of the invention in combination with an SSRI.
Combination administration can be carried out in a fashion analogous to that disclosed in Da-Rocha, et al., J. Psychopharmacology (1997) 11(3) 211-218; Smith, et al., Am. J. Psychiatry (1998) 155(10) 1339-45; or Le, et al., Alcohol and Alcoholism (1996) 31 Suppl. 127-132. Also see, the discussion of the use of the GABAA receptor ligand 3-(5 -methylisoxazol-3-yl)-6-(1-methyl-1,2,3-triazol-4-yl) methyloxy-1,2,4-triazolo [3,4-a]phthalazine in combination with nicotinic agonists, muscarinic agonists, and acetylcholinesterase inhibitors, in PCT International publications Nos. WO 99/47142, WO 99/47171, and WO 99/47131, respectively. Also see in this regard PCT International publication No. WO 99/37303 for its discussion of the use of a class of GABAA receptor ligands, 1,2,4-triazolo[4,3 -b]pyridazines, in combination with SSRIs.
The present invention also pertains to methods of inhibiting the binding of benzodiazepine compounds, such as Ro15-1788, to the GABAA receptors which methods involve contacting a compound of the invention with cells expressing GABAA receptors, wherein the compound is present at a concentration sufficient to inhibit benzodiazepine binding to GABAA receptors in vitro. This method includes inhibiting the binding of benzodiazepine compounds to GABAA receptors in vivo, e.g., in a patient given an amount of a compound of Formula I that would be sufficient to inhibit the binding of benzodiazepine compounds to GABAA receptors in vitro. In one embodiment, such methods are useful in treating benzodiazepine drug overdose. The amount of a compound that would be sufficient to inhibit the binding of a benzodiazepine compound to the GABAA receptor may be readily determined via an GABAA receptor binding assay, such as the assay described in Example 146. The GABAA receptors used to determine in vitro binding may be obtained from a variety of sources, for example from preparations of rat cortex or from cells expressing cloned human GABAA receptors.
The present invention also pertains to methods for altering the signal-transducing activity, particularly the chloride ion conductance of GABAA receptors, said method comprising exposing cells expressing such receptors to an effective amount of a compound of the invention. This method includes altering the signal-transducing activity of GABAA receptors in vivo, e.g., in a patient given a therapeutically effective amount of a compound of Formula I that would be sufficient to alter the signal-transducing activity of GABAA receptors in vitro. The amount of a compound that would be sufficient to alter the signal-transducing activity of GABAA receptors may be determined via a GABAA receptor signal transduction assay, such as the assay described in Example 147.
The GABAA receptor ligands provided by this invention and labeled derivatives thereof are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the GABAA receptor.
Labeled derivatives the GABAA receptor ligands provided by this invention are also useful as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT).
Definitions
If the compounds of the invention have asymmetric centers, then this invention includes all of the individual stereoisomers and mixtures thereof.
In addition, compounds with carbonxe2x80x94carbon double bonds may occur in cis, trans, Z- and E- forms, with all isomeric forms of the compounds being included in the invention.
When any variable (e.g. C1-6 alkyl, C1-8 alkyl, R1-R8, Ra, Rb, Rd, Rdxe2x80x2, Rdxe2x80x3, W, X, Y or Yxe2x80x2) occurs more than one time in Formula I, Formula II, IIa, IIb, IIc, IId, Formula III, IIIa, or Formula IV or any substituent definition, its definition on each occurrence is independent of its definition at every other occurrence. Thus, where a substituent definition carries two identical groups, e.g., xe2x80x94N(R2)2 or xe2x80x94N(alkyl) (alkyl), the definition of each R2 or alkyl group is independent of the other.
As used herein, the term xe2x80x9calkenylxe2x80x9d refers to a straight or branched hydrocarbon of a designed number of carbon atoms containing at least one carbonxe2x80x94carbon double bond. Examples of xe2x80x9calkenylxe2x80x9d include vinyl, allyl, and 2-methyl-3-heptenyl.
The term xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached to the parent molecular moiety through an oxygen atom. Examples of alkoxy groups include methoxy, ethoxy, propoxy and isopropoxy.
As used herein, the term xe2x80x9calkylxe2x80x9d includes those alkyl groups of the designated number of carbon atoms. Alkyl groups may be straight or branched. Examples of xe2x80x9calkylxe2x80x9d include methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, and the like. The terms alkyl1 and alkyl2 are used herein to designate alkyl groups that may be the same or different and have from 1-6 carbon atoms.
The term xe2x80x9calkynylxe2x80x9d refers to a straight or branched hydrocarbon of a designed number of carbon atoms containing at least one carbonxe2x80x94carbon triple bond. Examples of xe2x80x9calkynylxe2x80x9d include propargyl, propyne, and 3-hexynyl.
As used herein, xe2x80x9ccarbocyclic groupxe2x80x9d refers to aromatic carbocyclic ring systems and to cycloalkyl ring systems that have one or more double or triple bonds.
The term xe2x80x9carylxe2x80x9d is used to indicate aromatic groups that contain only carbon atoms in the ring structure. Thus, the term xe2x80x9carylxe2x80x9d refers to an aromatic hydrocarbon ring system containing at least one aromatic ring. The aromatic ring may optionally be fused or otherwise attached to other aromatic hydrocarbon rings or non-aromatic hydrocarbon rings. Examples of aryl groups are, for example, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene, indanyl, and biphenyl. Preferred examples of aryl groups include phenyl and naphthyl. The aryl groups herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. Thus, such aryl groups are optionally substituted with, for example, C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di(C1-C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, mono- or di(C1-C6)alkylamino(C1-C6)alkyl. Preferred W aryl groups are optionally substituted phenyl groups, where the substituents are as specified elsewhere herein. The term xe2x80x9ccycloalkenylxe2x80x9d refers to a C3-C8 cyclic hydrocarbon containing at least one carbonxe2x80x94carbon double bond. Examples of cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1,3-cyclohexadiene, cycloheptenyl, cycloheptatrienyl, and cyclooctenyl.
The term xe2x80x9ccycloalkylxe2x80x9d refers to a C3-C8 cyclic hydrocarbon. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
The term xe2x80x9ccycloalkynylxe2x80x9d refers to a C5-C10 cyclic hydrocarbon containing at least one carbonxe2x80x94carbon triple bond. Examples of cycloalkynyl include cyclohexynyl, cycloheptynyl and cyclodecynyl.
The term xe2x80x9chalogenxe2x80x9d indicates fluorine, chlorine, bromine, and iodine.
xe2x80x9cHaloalkylxe2x80x9d refers to branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms and substituted with 1 or more halogen atoms. Examples of haloalkyl include, but are not limited to, mono-, di-, or trifluoromethyl, mono-, di-, or trichloromethyl, mono-, di-, tri-, tetra-, or pentafluoroethyl, 3-bromopropyl, and mono-, di-, tri-, tetra-, or pentachloroethyl. Typical haloalkyl groups will have 1 to about 8 carbon atoms, more typically 1 to about 6 carbon atoms. Preferred haloalkyl groups are trifluoromethyl and 2,2-difluoroethyl.
xe2x80x9cHalolkoxyxe2x80x9d represents a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Preferred haloalkoxy groups are halo(C1-C6)alkoxy groups. Examples of haloalkoxy groups are trifluoromethoxy, 2,2-difluoroethoxy, 2,2,3-trifluoropropoxy and perfluoroisopropoxy.
As used herein, the terms xe2x80x9cheterocyclic groupxe2x80x9d or xe2x80x9cheterocycloalkylxe2x80x9d are intended to mean a stable 5-to 7 -membered monocyclic or bicyclic or 7-to 10-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and from 1 to 4 hetero atoms independently selected from N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur hetero atoms may optionally be oxidized. The term xe2x80x9cheteroarylxe2x80x9d is used to specifically indicate aromatic heterocyclic groups.
The heterocyclic ring may be attached to its pendant group at any hetero atom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and 0 atoms in the heterocycle exceeds 1, then these hetero atoms are not adjacent to one another. It is preferred that the total number of S and 0 atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d is intended to mean a stable 5-to 7-membered monocyclic or bicyclic or 7- to 10 -membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 hetero atoms independently selected from nitrogen, oxygen and sulfur. It is preferred that the total number of sulfur and oxygen atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothio-furanyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, benoztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, NHxe2x80x94carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl;- 1,2,5 -oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3 -thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4 -thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. The heterocycles herein are unsubstituted or, as specified, substituted in one or more substitutable positions with various groups. Thus, such heterocycles are optionally substituted with, for example, C1-C6 alkyl, C1-C6 alkoxy, halogen, hydroxy, cyano, nitro, amino, mono- or di-(C1-C6)alkylamino, C2-C6alkenyl, C2-C6alkynyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, amino(C1-C6)alkyl, mono- or di(C1-C6) alkylamino(C1-C6)alkyl. Preferred W heterocycle groups are optionally substituted pyridyl, pyrimidinyl, and thienyl groups, more preferably pyridyl groups, where the substituents are as specified elsewhere herein.
The formula: xe2x80x9cxe2x80x94CH2N(C2H5)CH2CH2N(C2H5)2xe2x80x9d as used in e.g., Example no. 116, represents a [(2-diethylamino-ethyl)-ethyl-amino]methyl group. This group can be represented by the formula: 
The formula: xe2x80x9cxe2x80x94CH2N(CH3)CH2CH2N(C2H5)2xe2x80x9d, as used, e.g., in Example no. 109, represents a [(2-diethylamino-ethyl)-methyl-amino]methyl group. This group can be represented by the formula: 
The formula: xe2x80x9cxe2x80x94CH2NCH2CH2N (C2H5)2xe2x80x9d represents a [2 -(diethylamino)ethylamino]methyl group. This group can be represented by the formula: 
Non-toxic pharmaceutically acceptable salts include, but are not limited to salts of inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, and nitric or salts of organic acids such as formic, citric, malic, maleic, fumaric, tartaric, succinic, acetic, lactic, methanesulfonic, p-toluenesulfonic, 2 -hydroxyethylsulfonic, salicylic and stearic. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts. The present invention also encompasses prodrugs of the compounds of Formula I.
The present invention also encompasses acylated prodrugs of the compounds of Formula I. Those skilled in the art will recognize various synthetic methodologies, which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by Formula I.
Pharmaceutical Preparations
Those skilled in the art will recognize various synthetic methodologies that may be employed to prepare non-toxic pharmaceutically acceptable prodrugs of the compounds encompassed by Formula I. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable solvents that may be used to prepare solvates of the compounds of the invention, such as water, ethanol, mineral oil, vegetable oil, and dimethylsulfoxide.
The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Oral administration in the form of a pill, capsule, elixir, syrup, lozenge, troche, or the like is particularly preferred. The term parenteral as used herein includes subcutaneous injections, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intrathecal injection or like injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of general Formula I may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compounds of general Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
For administration to non-human animals, a compound according to claim 1 or a pharmaceutically acceptable salt, with or without excipients, may be added to the animal""s feed or drinking water. It may be convenient to formulate these animal feed and drinking water compositions so that the animal ingests a therapeutically effective quantity of the compound of formula I or a pharmaceutically acceptable salt thereof, in a meal or during the course of a day. It may also be convenient to present the compound of formula I or a pharmaceutically acceptable salt thereof, as a premix for addition to the feed or drinking water.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of anxiety, depression, or cognitive impairment a dosage regimen of 1 or 2 times daily is particularly preferred. For the treatment of sleep disorders a single dose that rapidly reaches effective concentrations is desirable.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Preferred compounds of the invention will have pharmacological properties that include, but are not limited to, oral bioavailability, low toxicity, low serum protein binding and desirable in vitro and in vivo half-lives. Penetration of the blood brain barrier for compounds used to treat CNS disorders is generally necessary, while low brain levels of compounds used to treat peripheral disorders are often preferred.
Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocytes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously.
Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcovxc3xa1, et al. (Journal of Chromatography B (1996) volume 677, pages 1-27).
Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127).
Preparation of Compounds
A general illustration of the preparation of compounds of Formula I in the present invention is given in Scheme I and Scheme II: 
wherein the Ar ring, W, Ra, and Rb are as defined above in formula I, and Z is (CRaRb)n, wherein n is 1, 2, or 3.
In Scheme I BOP is benzotriazol-1 -yloxytris(dimethylamino)-phosphoniumhexafluorophosphate, TEA is triethylamine, DMF is N,N-dimethylformamide, EtOH is ethanol, and dioxane is 1,4-dioxane. Heat, as used herein, means elevated temperature, such as 40 to 250xc2x0 C. Those skilled in the art will recognize that it may be necessary to utilize different solvents or reagents to achieve some of the above transformations. 
wherein the Ar ring, W, Ra, and Rb are as defined above in formula I, and Z is (CRaRb)n, wherein n is 1, 2, or 3.
In Scheme II, TEA is triethylamine, BOP is benzotriazol-1-yloxytris(dimethylamino)-phosphoniumhexafluorophosphate, HCl is concentrated (12M) hydrochloric acid, DMF is N,N-dimethylformamide, and DMA is N,N-dimethylacetamide. Heat, as used herein, means elevated temperature, such as 40 to 250xc2x0 C. Those skilled in the art will recognize that it may be necessary to utilize different solvents or reagents to achieve some of the above transformations.
The invention is illustrated further by the following examples, which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present inventions, as demonstrated by the following examples. Unless otherwise specified all reagents and solvent are of standard commercial grade and are used without further purification. In some cases, protection of reactive functionalities may be necessary to achieve some of the above transformations. In general, such need for protecting groups, as well as the conditions necessary to attach and remove such groups, will be apparent to those skilled in the art of organic synthesis.